The present invention relates to novel diarylalkene derivatives and the use of the diarylalkene derivatives as medicines. The present invention also relates to novel diarylalkane derivatives and the use of the diarylalkane derivatives as medicines. It was suggested that N-type calcium channel is concerned with various diseases, for example, pain, brain injury caused by ischemia at the acute stage after the onset of cerebral infarction or cerebral hemorrhage (including subarachnoidal hemorrhage) or the like; progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia Parkinson's disease, dementia due to cerebrovascular disorder and ALS; neuropathy caused by head injury; various diseases associated with psychogenic stress such as bronchial asthma, unstable angina and irritable colitis; emotional disorder and withdrawal symptoms after addiction to drugs such as ethanol addiction withdrawal symptoms. The present invention relates to compounds antagonistic to the N-type calcium channel and, therefore usable as therapeutic agents for these diseases.
Calcium channels are now classified into subtypes of L, N, P, Q, R and T. Each subtype of calcium channels is organ-specifically distributed. It is known that particularly N-type calcium channel is widely distributed in central nerves, peripheral nerves and adrenomedullary cells and participates in neuronal cell death, regulation of blood catecholamine level and control of senses such as perception.
Omega conotoxin GVIA and omega conotoxin MVIIA are known as peptides selectively inhibiting N-type calcium channel. It was confirmed in animal tests that omega conotoxin MVIIA relieves a pain induced by formalin, hot plate and peripheral neuropathy (J. Pharmacol. Exp. Ther. 269, 1117-1123, 1994; J. Pharmacol. Exp. Ther. 274, 666-672, 1995). Accordingly, omega conotoxin MVIIA is considered to be clinically effective against pains. It was confirmed that omega conotoxin GVIA and omega conotoxin MVIIA inhibit the release of excitatory neurotransmitters in the sliced brain preparation. It was also confirmed in animal experiments that they inhibit the progress of neuronal cell death associated with cerebrovascular disorders. It is generally considered that compounds antagonistic to the N-type calcium channel are clinically effective in the treatment of brain injury caused by ischemia at the acute stage after the onset of cerebral infarction or cerebral hemorrhage (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia, Parkinson's disease, dementia due to cerebrovascular disorder and ALS; and neuropathy caused by head injury. In addition, because omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, the contraction of the isolated blood vessel by electric stimulation of the perivascular nerve and catecholamine secretion from canine adrenal medulla, it is considered that compounds antagonistic to N-type calcium channel are clinically effective against various diseases related to psychogenic stress such as bronchial asthma, unstable angina and irritable colitis [Neuropharmacol., 32, 1141 (1993)].
Some peptidergic and non-peptidergic compounds which selectively affect N-type calcium channels have been ever disclosed (see, for example, WO 9313128, WO 9849144, WO 9901438 and WO 9932446). However, none of them was actually used as a medicine. Some of the compounds which affect N-type calcium channels are also effective against various types of calcium channels of other than N-type (Br. J. Pharmacol., 122, 37-42, 1997). For example, compounds having an antagonistic effect on L-type calcium channels, which are very closely related to hypotensive effect, could not be used for assumed diseases for which N-type antagonists will be used (such as cerebral stroke, neuralgia, terminal cancer pain and pain caused by spinal injury). Under these circumstances, the development of a highly active antagonist selective toward N-type calcium channels has been eagerly demanded. In addition, an improvement in QOL (quality of life) of patients is demanded and the development of oral medicines is considered to be necessary.
However, well-known N-type calcium channel antagonists are yet insufficient for solving this problem, since some of them are peptides that cannot be absorbed from the gastrointestinal tracts or some are decomposed in the gastrointestinal tracts because of their chemical instability.
On the other hand, various diarylalkene derivatives and diarylalkane derivatives have been reported (WO 8803138, WO 9510516, WO 9630363, WO 95631478, U.S. Pat. No. 5,994,364 and Japanese Patent Kokai No. Hei 8-291142/1996). However, no literature disclosed that the compounds reported hereinbefore and also diarylalkene derivatives and diarylalkane derivatives analogous to them have a selective antagonistic effect on N-type calcium channel.
Piperidine derivatives having structures similar to those of the compounds of the present invention are reported in Japanese Patent Kokai No. Hei 8-3135/1996. However, it is also described therein that they are antithrombocytic agents which powerfully inhibit serotonin receptor 2, that because of the antagonistic effect on serotonin, they are effective in the treatment of ischemic diseases, migraine, etc. and that because of the antithrombocytic effect, they are effective in the treatment of a pain caused by various ischemic diseases and chronic arterial occlusive disease. However, it is to be noted that the compounds of the present invention are different from the piperidine derivatives disclosed in Japanese Patent Kokai No. Hei 8-3135/1996 because they scarcely have the antagonistic effect on serotonin.
Further, piperidine derivatives having structures similar to those of the compounds of the present invention and effective in the treatment of diseases such as asthma, allergic rhinitis, allergic dermatitis and hives are reported in Japanese Patent Kokai No. Hei 8-291142/1996. However, they are antihistaminic agents or antileukotrienes and essentially different, in the mechanism of the effects, from the N-type calcium channel antagonists directly effective on the neurons to exert the effects on the above-described diseases.